Veterinary medicine and especially in large animal practice, e.g., equine and bovine medicine and surgery, has incorporated various diagnostic, therapeutic and surgical procedures into the daily routine of the large animal practitioner. Many of these procedures are greatly facilitated and can be accomplished in the standing animal if the animal remains clam, motionless, and virtually pain free. An additional consideration is that it may also be beneficial to calm the animal, e.g., the cow or horse, before bringing it into proximity of expensive equipment or to minimize the potential for human injury.
Commonly used are sedatives which have a calming effect and tranquilizers which are a class of drugs used in the treatment of anxiety states. The goal of sedative and tranquilizer administration is to eliminate fear, produce a calming effect, reduce resistance to manipulation, and, to the extent there is an analgesic effect of the drug, to ideally eliminate pain. Generally, users or user facilities of such sedatives, tranquilizers and analgesics are veterinary hospitals, veterinarians working under field conditions, animal control facilities, humane societies, zoos, researchers and the like.
Classically, sedatives are a distinct groups of drugs based on their central nervous system (CNS) site of action. Sedatives are classically considered as agents that act at the cortical level and, if given in sufficient quantities, will produce CNS depression to the point of hypnosis (artificial sleep). Tranquilizers act at the sub-cortical levels, particularly at the reticular activating system, effectively filtering afferent and efferent nervous system activity. Increasing doses of tranquilizers produce greater degrees of calming but do not produce hypnosis. In practical use in animals, drugs acting at different levels of the CNS have been used to obtain the same result, thus the distinction often has become blurred and the term sedative-tranquilizer has evolved.
Alpha-2-adreno receptor agonists produce sedation, muscle relaxation and analgesia when administered intravenously or intramuscularly. Alpha-2-adreno receptor agonists are used to provide standing chemical restraint for various procedures, to provide analgesia, and to act as sedatives prior to anesthesia. The most commonly used alpha-2-agonists used, e.g., in the horse, are xylazine, detomidine and romifidine. All produce dose-dependent sedation and muscle relaxation whereas only xylazine and detomidine possess analgesic properties. The duration of action of these alpha-2-adreno receptor agonists, however is typically short, e.g., a single intravenous administration of 300 mg of xylazine in an adult horse produces moderate sedation and analgesia lasting from between about 30 to about 60 minutes. Therefore, there exists a need in the art for a long acting sedative and analgesic which can produce profound sedation and analgesia for longer periods of time following a single administration of the active.
Upon administration of the alpha-2-agonists, horses typically assume a wide stance with the head extended and lowered (ptosis). In male horses, some relaxation of the penis may occur and the lower lip becomes flaccid. Muscle relaxation and ataxia may be severe, particularly when large doses are administered. The effects of alpha-2-adreno receptor agonists can be specifically antagonized (reversed) by the administration of and alpha-2-adreno receptor antagonist (Hubbell J. A. E. and Muir W. W. Standing Chemical Restraint p. 187–192 in Equine Internal Medicine by Reed S. M and Bayly W. M, 1997)
Central alpha-2-adrenergic agonist cross the blood-brain barrier and stimulate alpha-2-adrenergic receptors in the vasomotor region of the brainstem. Stimulation Of these receptors decreases sympathetic tone, brain turnover of norepinephrine and central sympathetic outflow and activity of the preganglionic sympathetic nerves. The net effect is a reduction in norepinephrine release. Central alpha-2-adrenergic agonist may also stimulate the peripheral alpha-2-adrenergic receptors that mediate vasoconstriction. The usual physiologic effect is a decrease in peripheral resistance and slowing of the heart rate; however, output is either unchanged or mildly decreased. Preservation of cardiovascular reflexes prevents postural hypertension.
In human medicine, a variety of guanidine derivatives have been used clinically as anti-hypertensive agents, including clonidine, guanabenz, guanacline, guanadrel, guanazodine, guanethidine, guanfacine and guanochlor, guanoxabenz and guanoxan.
Guanabenz (1-[2,6-dichlorobenzylidine-amino]-3-guanidine) is an anti-hypertensive drug whose mechanism of action is an agonistic stimulatory effect of the central alpha-2 adrenergic receptors in the cardiovascular regulatory centers in the brainstem and spinal cord. Its therapeutic effects in humans include a reduction in sympathetic tone (a reduction in heart rate and cardiac output), an increase in parasympathetic tone (a reduction in heart rate and cardiac output) and vasodilation (a relaxation of capacitance vessels and reduction in total peripheral resistance). Guanabenz is currently marketed in human medicine in the general class of medicines called antihypertensives. It is used to treat high blood pressure (hypertension). Guanabenz acetate is available on the market as 4 and 8 mg tablets to be taken orally, e.g., as WYTENSIN® (Wyeth-Ayerst, Alexandria, Va.)
Certain uses of guanabenz have been previously disclosed in the art. For example, U.S. Pat. No. 4,060,640, to Kodama et al., describes guanabenz, and its related compounds, as being central nervous system depressants that reduce hyperexcitability and induce sedation, overcoming psychic depression in humans.
U.S. Pat. No. 5,958,933 to Naftchi discloses guanabenz, as part of a drug combination, as being a neurologically active compound that when administered in an appropriate dosage amount is sufficient to restore neurological function or control spasticity in humans suffering from injury to the central nervous system.
U.S. Pat. No. 4,742,054 to Naftchi discloses guanabenz to have a restorative effect on the central nervous system, especially in the treatment in mammals of motor and sensory functional losses due to the traumatic injury to the spinal cord. Guanabenz is described as being an effective anaesthetic compound and for use in a method for treating a mammal having a damaged central nervous system.
U.S. Pat. No. 5,635,204 to Gevirtz et al. discloses guanabenz, in combination with other drugs at a particular dosage as being an effective anaesthetic.
U.S. Pat. No. 5,958,933, to Naftchi describes oral over-dosage of guanabenz, as not being reported to result in anesthesia; the incidents were recorded as hypotension, somnolence, lethargy, irritability, myosis and bradycardia in young children.
In veterinary medical applications, equine racetrack veterinarians have previously used an 8 mg tablet of guanabenz, crushed and dissolved in water, and injected the resultant solution intravenously into horses prior to racing. The rationale behind this administration is that it reduces the blood pressure in the horse's pulmonary circulatory tract and thereby reduces the incidence and/or severity of exercise induced pulmonary hemorrhage (EIPH) in the horse.
Current available sedatives and tranquilizers such as the aforementioned xylazine and detomidine can produce side effects such as sinus bradychardia and first or second degree atrioventricular block (Bohart G. Anesthesia of Horses in the Field in Current Therapy in Equine Medicine by Robinson N. E, 1998.). Therefor there exists a need in the art for a safe, effective oral, intravenous, or intramuscular compound for the standing sedation, tranquilization and analgesic effect of larger mammals that does not produce the adverse side effects seen with current sedatives/tranquilizers.
Prior to the present invention guanidine derivatives, and in particular guanabenz and its analogs, have not been reported as useful as a standing sedative, tranquilizer and analgesic combination when used in horses and lower mammals at certain dosages.